Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) are common viruses that afflict millions of Americans. Infection with HCV causes progressive liver fibrosis, which frequently results in end-stage liver disease and hepatocellular carcinoma. The course of HCV is worsened by co-infection with HIV. The mechanism by which HIV exacerbates HCV liver disease is still not known. We demonstrate that 1) livers from HCV mono-infected patients have elevated expression of TRAIL (TNF- related apoptosis inducing ligand) and 2) HIV envelope gp120 binding to the chemokine receptor CXCR4 induces a G-protein independent, JNK dependent, TRAIL-R2 upregulation and acquired sensitivity to TRAIL-induced death. These observations allow us to propose the following model of HCV/HIV co-infection that is responsible for enhanced liver disease in co-infected people: (i) HCV infection enhances TRAIL expression in hepatocytes, (ii) HIV infection increases TRAIL-R2 expression and confers TRAIL sensitivity in hepatocytes, and that (iii) HCV and HIV co-infection consequently results in TRAIL-dependent hepatotoxicity. The current proposal will evaluate this conceptual model to explain the enhanced liver disease progression in HCV/HIV co-infected people through the following hypothesis-driven specific aims. [unreadable] [unreadable] [unreadable]